Case Report
Novichok nerve agent poisoning
David Steindl, Wolfgang Boehmerle, Roland Körner, Damaris Praeger, Marcel Haug, Jens Nee, Adrian Schreiber, Franziska Scheibe,
Katharina Demin, Philipp Jacoby, Rudolf Tauber, Sven Hartwig, Matthias Endres, Kai-Uwe Eckardt
On Aug 20, 2020, a 44-year-old man who was previously
healthy suddenly became confused and began to sweat
heavily on a domestic flight in Russia approximately
10 min after departure; he vomited, collapsed, and lost
consciousness. After an emergency landing, the man
was admitted to the toxicology unit of a local hospital in
Omsk, Russia, approximately 2 h after symptom onset.
According to the discharge report, the patient presented
comatose with hypersalivation and increased diaphoresis
and was diagnosed to have respiratory failure, myoclonic
status, disturbed carbo­ hydrate metabolism, electrolyte
disorders, and metabolic encephalopathy. Therapeutic
measures included intuba­tion, mechanical ventilation,
and unspecified drugs for symptom control and
neuroprotec­ tion. On Aug 22, 2020, the patient was
transferred by a German air ambulance to the Charité-
Universitätsmedizin Berlin at the request of his family.
Severe poisoning with a cholinesterase inhibitor was
sub­sequently diagnosed. 2 weeks later, the German
Government announced that a laboratory of the
German armed forces designated by the Organization for
the Prohibition of Chemical Weapons (OPCW) had
identified an organophosphorus nerve agent from the
novichok group in blood samples collected immediately
after the patient’s admission to Charité,1 a finding that
was subsequently confirmed by the OPCW.2 Here, we
report clinical details of this case.
Clinical course
Approximately 31 h after symptom onset, a doctor from the
German air ambulance crew had temporary access to the
patient and recorded bradycardia (44 beats per min [bpm]),
hypothermia (34·4°C), wide pupils non-reactive to light,
and intermittent myoclonus under sedation with propofol,
the only obvious drug given at that time. Peripheral oxygen
saturation was 100% while the patient was on pressure-
regulated volume control ventilation with low positive end-
expiratory pressure and a fractional concentration of
oxygen in inspired air (FiO2) of 30%. 16 h later, when the
patient was handed over to the German air ambulance
crew for transportation to Berlin, his condition had slightly
improved (pupils constricted, heart rate 59 bpm). Propofol
was again the only drug administered at that time.
During subsequent airborne transport in an EpiShuttle
isolation system (EpiGuard, Oslo, Norway), the patient
received propofol, fentanyl, and crystalloids and continued
to be ventilated with 30% FiO2. On arrival at an intensive
care unit at Charité, approximately 55 h after symptom
onset, the patient was deeply comatose, with mild
bradycardia (51 bpm, subsequently declining to 33 bpm),
hypersalivation, hypothermia (33·5°C), increased diapho­
resis and small pupils not reactive to light, decreased
www.thelancet.com Published online December 22, 2020 https://doi.org/10.1016/S0140-6736(20)32644-1 1
brainstem reflexes, hyperactive deep tendon reflexes, and Published Online
pyramidal signs. Laboratory analyses showed substan­ December 22, 2020
https://doi.org/10.1016/
tially decreased levels in plasma of butyrylcholinesterase S0140-6736(20)32644-1
(also called pseudocholinesterase) and increased levels of
See Online/Comment
amylase, lipase, high-sensitivity troponin T, and sodium https://doi.org/10.1016/
in plasma (appendix p 1). Based on clinical and laboratory S0140-6736(20)32749-5
findings, severe cholinesterase inhibition was diagnosed Department of Nephrology
and the patient was started on atropine and obidoxime and Medical Intensive Care
(D Steindl MD, R Körner MD,
(250 mg bolus followed by continuous administration
J Nee MD, A Schreiber MD,
of 750 mg per day). Cholinergic signs returned to normal Prof K-U Eckardt MD),
within 1 h after the onset of this antidotal therapy. Analgo­ Department of Neurology
sedation with sufentanil and propofol was sup­plemented (W Boehmerle MD,
F Scheibe MD,
with midazolam for neuroprotection.3
K Demin Dr rer medic,
Toxicological analysis and drug screening in blood and Prof M Endres MD), Department
urine samples obtained on admission to the intensive of Cardiology and Angiology
care unit at Charité identified several drugs, including (D Praeger MD, M Haug MD),
Institute of Legal Medicine and
atropine, which we attributed to the previous treatment
Forensic Sciences
the patient had received in the intensive care unit (S Hartwig MD), and Institute of
in Omsk before the medical transfer to Germany Laboratory Medicine, Clinical
(appendix p 2). Testing for cholinesterase status4 in a Chemistry and
Pathobiochemistry
specialised external laboratory showed complete inhi­ (Prof R Tauber MD),
bition of acetylcholinesterase in red blood cells, thereby Charité-Universitätsmedizin
con­firming the exposure to a cho­lin­esterase inhibitor, Berlin, Berlin, Germany; Flight
and no evidence for reactivation by obidoxime or free Ambulance International,
Nürnberg, Germany
unbound cholinesterase inhibitor in plasma (appendix (P Jacoby MD); Labor Berlin
p 3). Accordingly, obidoxime was stop­ped after 1 day.5 Charité Vivantes GmbH, Berlin,
Atropine was continued for 10 days and titrated to Germany (Prof R Tauber)
suppress cholinergic symptoms (figure 1). On day 5, the Correspondence to:
patient developed a fever that was treated with external Prof Kai-Uwe Eckardt,
Department of Nephrology and
cooling for 9 days and subsequently with anti­ pyretic Medical Intensive Care,
therapy using pethidine, metamizole, and para­cetamol. Charité-Universitätsmedizin
Intermittent myoclonic muscular contrac­tions, pre­domi­ Berlin, 10117 Berlin, Germany
nately of the thoracic and abdominal muscles, responded nephro-intensiv@charite.de
poorly to atropine and increased sedation and persisted See Online for appendix
for up to 15 days.
Cranial CT and MRI scans, analysis of cerebrospinal
fluid, short-latency somatosensory evoked potentials,
and plasma neuron-specific enolase concentration on
day 4 were all within normal ranges, and an electro­­­
encepha­lo­gram was consistent with sedation. Electrophys­
io­
logical examinations showed the specific kind of
dys­function of neuromuscular transmission that is
typical for cholinesterase inhibition. Repetitive responses
were noted after a single supramaximal elec­ trical
stimulus (figure 2A). Repeated nerve stimulation showed
a decrement-increment response pattern at fre­quen­cies
of 10 Hz or greater, which was more pronounced at
higher stimula­tion frequencies (figure 2B, 2C), con­sistent
with blockade of neuromuscular transmission caused by
depolarisa­­tion.6 Stimulated single-fibre electro­myography
showed prolonged variation in the time between action
potentials of the same motor unit, which is called jitter
 Case Report

Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

Ventilation Continuous ventilation Spontaneous breathing

Pyrexia

Myoclonus

Atropine ? ?

Antibiotics ? ?

8·0
Butyrylcholinesterase (kU/L) 4·0
0·0
400
C-reactive protein (mg/L) 200
0
400
γ glutamyl transferase (U/L) 200
0
40
Plasma albumin (g/L)
20
Dilatational tracheostomy Assisted spontaneous breathing
Decannulation Myoclonus
Spontaneous breaths ? Timing and duration of atropine application and antibiotic therapy before admission to ICU at Charité is
Spontaneous breathing trial uncertain
Administration of 6 units of fresh-frozen plasma

Figure 1: Schematic presentation of the clinical course

Figure shows selected clinical findings, treatment aspects, and laboratory values during the patient’s stay in intensive care (days 1–25) and on a regular hospital ward
(days 26–33). Symbol sizes provide a semiquantitative estimate. Trends of laboratory findings recorded at Charité are displayed as area charts; values are provided in
the appendix (p 4).

(figure 2D). These findings improved continuously
within the next 7 days (figure 2A, 2C, 2D).
During the period in the intensive care unit at Charité,
the patient temporarily showed signs of systemic inflam­
ma­tion and increases in liver enzymes (figure 1; appendix
p 4). Activity of butyrylcholinesterase in plasma started
to increase on day 4 but plateaued on day 6 at levels
below normal, which prompted us to administer 6 units
of fresh-frozen plasma; this transfusion led to a pro­
nounced increase in activity with no subsequent decline,
thus excluding consumption of butyryl­cholin­esterase by
unbound inhibitory nerve agent in blood, consistent with
findings of in vitro testing (appendix p 3). On day 10, the
spontaneous increase in plasma butyrylcholinesterase
activity resumed, and values within the normal range
were reached on day 20 (appendix p 4). By comparison,
activity of acetylcholinesterase in red blood cells recov­
ered more slowly and only partly until day 21 (appendix
p 3). The patient’s haemoglobin concentration dropped
from 12·2 g/dL to 7·5 g/dL and recovered after intra­
venous iron and oral folate supplementation.
In skin swabs obtained on admission to the intensive
care unit at Charité, we noted colonisation with five
different multi­ drug-resistant bacteria: Staphylococcus
aureus, Acinetobacter baumannii complex, Pseudomonas
aeruginosa, Escherichia coli, and Klebsiella pneumoniae.
Microbial characterisation of subsequent rectal swabs
and urine samples showed two different variants of
K pneumoniae. Based on these findings, we used
antibiotics very reluctantly. A urinary tract infection with
K pneumoniae was treated with co-trimoxazole, and
a possible bloodstream infection with Staphylococcus
epidermidis was treated with a 4-day course of vanco­
mycin. CT on admission and plain chest radiography on
days 3, 5, 9, 10, and 13 showed no clear signs of pulmonary
infiltration. Because of purulent bronchoalveolar fluid
in conjunction with increased levels of C-reactive protein,
the patient received colistin inhalations for 9 days, sub­
sequently tapered to prophylactic doses.
During the patient’s stay in intensive care at Charité, gas
exchange was never severely impaired. FiO2 was usually
below 40%, except on day 9, when it was temporarily
increased to 50%. We did a percutaneous dilatational
tracheostomy on day 13 in anticipation of complicated
weaning. On day 12, the patient started to breathe spon­
taneously (figure 1) and could subsequently be weaned
from mechanical ventilation completely by day 24. He
gradually recovered from a delirium and was mobilised
and transferred to a regular hospital ward on day 26. At
discharge on day 33, a neurological examination showed
enhanced physio­ logical tremor and hyperactive deep
tendon reflexes but neither pyramidal signs nor evidence
of polyneuropathy. Neuropsycholo­gical testing performed
in Russian, the patient’s native language, showed subtle

2 www.thelancet.com Published online December 22, 2020 https://doi.org/10.1016/S0140-6736(20)32644-1

 Case Report

impairments in processing speed and verbal fluency,

A B
which had completely resolved 3 weeks later. At the last Day 5 Day 12 Day 55 10 Hz 20 Hz
follow-up visit on day 55 we found near-complete recovery 20
of neurological, neuro­ psychological, and neurophysi­ –10 000
ological findings without evidence of polyneuropathy. 15
–5000

CMAP (mV)
CMAP (μV)
Discussion 0 10
Novichoks are a group of nerve agents developed
in the former Soviet Union in the 1980s.7 Five recent 5
cases of novichok poisoning, including one fatal, have
been reported in the UK.7,8 However, up to now, no 0
clinical details have been published. 0 20 40 60 1 2 3 4 5 6 7 8 9 10
Time (ms) Stimulus number
Identification of an individual organophosphorus
com­pound is a complex and time-consuming process.9 C D
In fact, ascertaining the involvement of a novichok agent 3 Hz 10 Hz 20 Hz
and its biotransformation products in this case was only 30 Hz 50 Hz
40 200
achieved several days after establishing the diagnosis of
Change in CMAP impulse 1–5 (%)

cholin­ esterase inhibitor poisoning and did not affect 20

Jitter in abductor pollicis

150
therapeutic decisions.

brevis muscle (μs)

Organophosphorus nerve agents exert the same
mechanism of action as do organophosphorus pes­ ti­
cides (ie, inhibition of acetylcholinesterase) and clinical
manage­ment is largely based on experience with organo­
phosphorus pesticide poisonings, which still pose
a major health burden in southeast Asia, with more
than 100 000 deaths per year.10 Clinical diagnosis of
organophosphorus poisoning should be straightforward.
The range of findings caused by overstimulation of
muscarinic and nicotinic receptors seen in our patient
was in line with published literature: miosis, conjunctival
injection, hypersalivation, diaphoresis, bradycardia, and
elevation of plasma lipase and amylase, which are
attributed to pancreatic and salivary gland stimulation,
hyperactive deep tendon reflexes, pyramidal signs,
and prolonged muscular hyperactivity.11 Moreover,
we observed typical pathological changes in electro­
physio­logy and single-fibre electromyography studies.12,13
After normalisation of neuromuscular transmission, the
patient started to breathe spontaneously on day 12.
Tests for butyrylcholinesterase activity, which are
primarily used as a liver function test, are widely available
in clinical routine practice and are usually the only
laboratory parameter to confirm a clinical diagnosis
of organophosphorus poisoning. The cholinesterase
status provides additional important information for
thera­peutic decisions, such as the presence of unbound
acetyl­cholinesterase inhibitor in patient’s plasma and
the possibility to reactivate organophosphorus–acetylcho­
linesterase conjugates with a particular oxime (appendix
p 3).4 In fact, absence of inhibitory activity in our patient’s
plasma in conjunction with inability to reactivate
acetylcholinesterase in red blood cells prompted early
termination of obidoxime. Consistent with findings
of experimental and clinical studies, suf ­fi cient muscle
function enabling spontaneous breathing on day 21
correlated with approximately 30% activity of acetylcho­
linesterase in red blood cells (figure 1; appendix p 3).14
0
100
–20
50
–40
–60 0
Day 5 Day 8 Day 12 Day 5 Day 8
Figure 2: Selection of key electrophysiological findings in the abductor pollicis brevis muscle
(A) Repetitive responses were noted after a single supramaximal electrical stimulus, which disappeared at
follow-up. On day 55, normalised CMAP was seen. (B) Repetitive nerve stimulation of the median nerve on day 5
showed a decrement-increment pattern at frequencies ≥10 Hz, which was more pronounced at higher stimulation
frequencies; (C) this finding continuously improved within the next 7 days. (D) Stimulated single-fibre
electromyography with concentric needles showed increased jitter; line shows median, boxes the IQR, and error
bars the range; dashed line represents upper limit of normal for individual jitter values. CMAP=compound motor
action potential.
Additional findings with less clear pathophysiology
have previously been described in organophosphorus
poisoning. Among these was a refractory disturbance
of thermoregulation with initial hypothermia followed
by fever. Hypothermia during the early course might, in
part, have been caused by increased diaphoresis, whereas
side-effects of atropine, infectious complications, and
unknown factors are considered to cause subsequent
fever.15 We also recorded a transient rise of troponin in
conjunction with repolarisation disturbances on electro­
cardiogram in the presence of normal echocardiography,
consistent with cardiotoxicity of nerve agents.16 Signs
of hepatic injury with increases of aminotransferases
and γ glutamyl transferase have also previously been
reported4,17 and, in part, been attributed to obidoxime,18
which our patient received for less than 24 h. An
unexplained finding seen in this case was pronounced
transi­ent hypoalbuminaemia, which could not be attribu­
ted to enteric or renal loss or impaired liver function.
Our patient had a very favourable outcome. Pre­
sumably, intubation and mech­­anical ventilation within
2–3 h of symptom onset and absence of preceding
severe hypoxia were decisive. Onset and duration of
atropine therapy during the first 2 days remain unclear.

www.thelancet.com Published online December 22, 2020 https://doi.org/10.1016/S0140-6736(20)32644-1 3

 Case Report
Fortunately, despite a high risk for aspiration during
the initial period of unconsciousness, and colonisation
with several multidrug-resistant bacteria, the patient did
not develop severe infection. His good health status
before the poisoning probably favoured his recovery.
Contributors
DS and K-UE wrote the first draft of the report, coordinated internal
revision, and prepared the submitted version. All authors contributed to
data collection, data analysis, and data interpretation. RK, DP, MH, JN,
AS and PJ were responsible for defined periods of treatment. WB, FS,
and ME performed neurological and neurophysiological assessments.
KD and ME did neuropsychological assessments. RT was responsible for
clinical chemistry. SH did toxicological analyses. All authors vouch for
accuracy of the data. DS and K-UE had unlimited access to all clinical
data and reports.
Declaration of interests
We declare no competing interests.
Acknowledgments
This report was prepared using internal resources without specific
funding. We gratefully acknowledge the support from many colleagues
in the assessment and interdisciplinary management of this case,
including members of the Bundeswehr Institute of Pharmacology and
Toxicology in Munich, Germany, who did repetitive measurements of
butyrylcholinesterase, acetylcholinesterase in red blood cells, and
cholinesterase status and gave toxicological advice.
References
1 Seibert S. Statement by the Federal Government on the Navalny
case. Sept 2, 2020. https://www.bundeskanzlerin.de/bkin-en/
homepage/statement-by-the-federal-government-on-the-navalny-
case-1781882 (accessed Dec 3, 2020).
2 OPCW Technical Secretariat. Summary of the report on activities
carried out in support of a request for technical assistance by
Germany (technical assistance visit—TAV/01/20). Oct 6, 2020.
https://www.opcw.org/sites/default/files/documents/2020/10/
s-1906-2020%28e%29.pdf (accessed Dec 3, 2020).
3 Hulse EJ, Haslam JD, Emmett SR, Woolley T. Organophosphorus
nerve agent poisoning: managing the poisoned patient.
Br J Anaesth 2019; 123: 457–63.
4 Thiermann H, Mast U, Klimmek R, et al. Cholinesterase status,
pharmacokinetics and laboratory findings during obidoxime
therapy in organophosphate poisoned patients.
Hum Exp Toxicol 1997; 16: 473–80.
4 www.thelancet.com Published online December 22, 2020 https://doi.org/10.1016/S0140-6736(20)32644-1
5 Amend N, Langgartner J, Siegert M, et al. A case report of
cholinesterase inhibitor poisoning: cholinesterase activities and
analytical methods for diagnosis and clinical decision making.
Arch Toxicol 2020; 94: 2239–47.
6 Maselli RA, Leung C. Analysis of neuromuscular transmission
failure induced by anticholinesterases. Ann N Y Acad Sci 1993;
681: 402–04.
7 Vale JA, Marrs TC, Maynard RL. Novichok: a murderous nerve
agent attack in the UK. Clin Toxicol 2018; 56: 1093–97.
8 OPCW Technical Secretariat. Summary of the report on activities
carried out in support of a request for technical assistance by the
United Kingdom of Great Britain and Northern Ireland (technical
assistance visit TAV/03/18 and TAV/03B/18 “Amesbury incident”).
Sept 4, 2018. https://www.opcw.org/sites/default/files/
documents/2018/09/s-1671-2018%28e%29.pdf (accessed Dec 3, 2020).
9 John H, van der Schans MJ, Koller M, et al. Fatal sarin poisoning in
Syria 2013: forensic verification within an international laboratory
network. Forensic Toxicol 2018; 36: 61–71.
10 Mew EJ, Padmanathan P, Konradsen F, et al. The global burden of
fatal self-poisoning with pesticides 2006–15: systematic review.
J Affect Disord 2017; 219: 93–104.
11 Grob D. The manifestations and treatment of poisoning due to
nerve gas and other organic phosphate anticholinesterase
compounds. AMA Arch Intern Med 1956; 98: 221–39.
12 Besser R, Gutmann L, Dillmann U, Weilemann LS, Hopf HC.
End-plate dysfunction in acute organophosphate intoxication.
Neurology 1989; 39: 561–67.
13 Thiermann H, Zilker T, Eyer F, Felgenhauer N, Eyer P, Worek F.
Monitoring of neuromuscular transmission in organophosphate
pesticide-poisoned patients. Toxicol Lett 2009; 191: 297–304.
14 Thiermann H, Eyer P, Worek F. Muscle force and
acetylcholinesterase activity in mouse hemidiaphragms exposed to
paraoxon and treated by oximes in vitro. Toxicology 2010; 272: 46–51.
15 Moffatt A, Mohammed F, Eddleston M, Azher S, Eyer P, Buckley NA.
Hypothermia and fever after organophosphorus poisoning in
humans: a prospective case series. J Med Toxicol 2010; 6: 379–85.
16 Cha YS, Kim H, Go J, et al. Features of myocardial injury in severe
organophosphate poisoning. Clin Toxicol 2014; 52: 873–79.
17 Yu S, Yu S, Zhang L, et al. Efficacy and outcomes of lipid
resuscitation on organophosphate poisoning patients: a systematic
review and meta-analysis. Am J Emerg Med 2019; 37: 1611–17.
18 Eyer F, Worek F, Eyer P, et al. Obidoxime in acute organophosphate
poisoning: 1—clinical effectiveness. Clin Toxicol 2009; 47: 798–806.
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